Hepatocellular carcinoma (HCC) is a significant health problem in the United States. Compared to European Americans (EA), the incidence of HCC is higher in African Americans (AA) and is associated with more advanced tumor stage at diagnosis and lower survival rates. It has been reported that the sensitivity of ?- fetoprotein (AFP) for the diagnosis of HCC in African Americans with hepatitis C virus (HCV) infection is lower than that of patients of all other racial groups combined. We previously performed preliminary investigation into racial disparities through metabolomics profiling of sera from HCC cases and patients with liver cirrhosis by using both liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS). Through stratified analysis of the LC/GC-MS data, we identified different candidates that distinguish HCC cases from the cirrhotic controls among AA and EA. This application builds on these promising preliminary results to find and validate race-specific metabolites as biomarkers for HCC. This will be accomplished by targeted analysis of metabolites in liver tissues and sera from HCC cases and patients with liver cirrhosis representing AA and EA. Metabolites that differentiate HCC cases from cirrhotic controls in a race-specific manner will be selected by statistical and network-based methods. Then, a systems-oriented approach that combines these metabolites with other candidate biomarkers (genes, glycans, and proteins) will be utilized for the selection of key signaling pathways perturbed in HCC. Following validation of the candidates via independent samples from HCC cases, patients with liver cirrhosis, and healthy subjects, we will elucidate their functional roles through both in vitro and in vivo experiments. Successful completion of this research will enable us to identify HCC biomarkers and perturbed pathways that are race-specific as well as those that are shared by AA and EA. These findings will contribute not only to a greater understanding of racial disparities in HCC but also to improving diagnosis of HCC through race-specific biomarkers.